Solid oral dosage forms containing oxcarbazepine (OXC; 10,11-Dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide; disclosed in U.S. 2004-0044200A1, U.S. Pat. No. 3,642,775 and U.S. Pat. No. 3,716,640) are known (FDA Electronic Orange Book). OXC is susceptible to hydrolysis under basic/alkaline conditions. Oxcarbazepine is a prodrug that is quickly reduced to a 10-monohydroxy metabolite derivative (MHD) which is the active metabolite.
OXC is an antiepileptic indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and as monotherapy in the treatment of partial seizures in children aged 4 years and above with epilepsy, and as adjunctive therapy in children aged 2 years and above with epilepsy.
OXC is hydrophobic and poorly water soluble and must be present in very small particles sizes when administered as a solid oral dosage form in order to provide sufficient absorption of drug. U.S. Pat. No. 7,037,525 specifies oxcarbazepine having a particle size such that the maximum residue on a 40 micron sieve is less than or equal to 5% and the median particle size is approximately 2 to 12 microns, or 4 to 10 microns or 6 to 8 microns. EP 2,010,499 A1 discloses oxcarbazepine having a particle size distribution with a D[v,0.5] value of between about 15 microns to about 30 microns and a D[v,0.9] value of less than or equal to 90 microns. U.S. Pat. No. 8,119,148 discloses OXC wherein the quantity of particles larger than 40 micrometers (μm) is limited to a maximum of 5% by weight and the median particle size by Fraunhofer diffraction is specified to be within 4-10 μm. EP 2,077,822 discloses OXC with a median particle size of 4-10 μm. PCT Publication WO 2007-007182 discloses OXC with a median particle size in the range of 15 to 30 μm and wherein the composition contains no wetting agent. PCT Publication WO 2006-046105 discloses OXC with a median particle size in the range of 15 to 30 μm and wherein the composition contains no wetting agent. PCT Publication WO 2002-094774 discloses OXC with a median particle size of about 20 μm to about 50 μm with a maximum residue of about 10% on a 45 μm to up to 100 μm sieve and wherein a wetting agent is present. Indian Application No. 1186/MUM/2004 discloses a pharmaceutical composition containing oxcarbazepine particles and meglumine, which aids in dissolution of the drug, wherein the oxcarbazepine has a particle size of not less than 50 μm or about 80 to 140 μm. EP 2,146,699 A1 discloses dosage forms containing oxcarbazepine having a median particle size of about 2 μm or less.
OXC is dosed orally according to a twice daily regimen (BID) at doses of 300 to 2400 mg per day for the treatment of epilepsy. When a unit dose includes 150 to 1200 mg of OXC, young and elderly patients typically experience difficulty in swallowing solid oral dosage forms containing such high doses, especially because of the large amount of excipients included in known dosage forms. Difficulty in swallowing leads to poor patient compliance. Attempts to resolve this problem have led to the development of oral liquid formulations. Stability, contamination and inaccurate dosing problems, however, are still associated with such dosage forms.
Given the high doses of OXC required per tablet, it is difficult to formulate rapidly dispersible solid oral dosage forms with sufficient hardness and friability suitable for storage and handling while at the same time providing a dosage form that is small enough for easy swallowing.
Orodispersible dosage forms disperse or disintegrate in the mouth in a minimal amount of saliva or water. Such dosage forms provide ease of swallowing, accuracy of dosing, and rapid therapeutic action. U.S. Pat. No. 7,749,533 to Fu et al. discloses a dosage form containing granules containing a drug, porous plastic substance, water penetration enhancer, binder and drug. The granules must be compressed in order to create the dosage form. U.S. Pat. No. 4,371,516 to Gregory et al. and U.S. Pat. No. 5,738,875 disclose freeze-dried dosage forms. U.S. Pat. No. 5,178,878 to Wehling et al. discloses a soft-compress orodispersible dosage form. Effervescent dosage forms and quick release coatings of insoluble microparticles are described in U.S. Pat. Nos. 5,578,322 and 5,607,697. Freeze dried foams and liquids are described in U.S. Pat. No. 4,642,903 and U.S. Pat. No. 5,631,023. Melt-spun dosage forms are described in U.S. Pat. Nos. 4,855,326, 5,380,473 and 5,518,730. U.S. 20070218129 discloses an immediate release dispersible and orodispersible solid pharmaceutical composition having the form of particles with a size lower than 710 μm upon dispersion into water, wherein the formulation is made by wet granulation; however, the disintegration times range from 53 to 60 sec.
U.S. Pat. No. 6,471,992, U.S. 2012-0207929 and U.S. 2003-0133975 disclose three-dimensionally printed rapidly dispersing dosage forms. Even so, an orodispersible three-dimensionally printed dosage form containing OXC has not been suggested. It is not possible to predict a priori whether a three-dimensionally printed dosage form containing substantial amounts of OXC can be made to disperse in a minimal amount of aqueous fluid in 10 sec or less or 5 sec or less while at the same time possessing sufficient hardness to endure handling and storage.
Very few orodispersible dosage forms containing OXC have been disclosed or suggested. U.S. Pat. No. 8,127,516 and U.S. 20120110957 to Lee suggest a film-coated tablet or film-coated powder fill. U.S. Pat. No. 8,012,505 and U.S. 20040228919 to Houghton suggest a freeze-dried non-compressed fast-dispersing solid dosage form. U.S. Pat. No. 6,709,669 and U.S. Pat. No. 6,509,040 to Murray and U.S. 20040076666 to Green suggest a freeze-dried non-compressed fast-dispersing solid dosage form having fish gelatin as carrier. U.S. 20080312168 to Pilgaonkar discloses a dispersible compressed tablet that disperses in water in three minutes. The tablet contains oxcarbazepine, Copovidone (Kollidon VA 64), microcrystalline cellulose (Avicel PH 102), Sodium starch glycolate (Primojel), Crospovidone (Kollidon CL), Hydroxypropylmethylcellulose (Methocel K100 LV), Hydroxyethylcellulose (Natrosol HHX), Aerosil, Talc and magnesium stearate.
It would be beneficial to provide a rapidly-dispersing solid oral dosage form containing a high concentration of OXC and exhibiting low friability and sufficient hardness to withstand storage and handling while at the same time exhibiting an extremely rapid disintegration rate and acceptable taste; however, no such suitable dosage form has been suggested in the art. In particular, no such three-dimensionally printed dosage form has been suggested.